DESCRIPTION, OVERALL (provided by applicant): This is a proposal to continue our Cystic Fibrosis (CF) Research and Translational Core Center at the University of California, San Francisco and collaborating institutions. The focus of our Core Center remains the discovery and evaluation of novel small-molecule therapies for CF. The original proposal followed from 5 years of work establishing a unique academic drug discovery program in the laboratories of Dr. Verkman and collaborators to identify and characterize small-molecule modulators of CFTR activity. The proposed Core Center will fund five Cores to support the activities of 2 Pilot Projects and 28 CF-related projects. The Core directors are experienced CF investigators with recognized expertise in their areas of investigation and a history of productive collaboration. The Cores include: High-Throughput Screening (Core A, Alan Verkman, director), Clinical Resources (Core B, Dennis Nielson, director), Cell Models (Core C, Walter Finkbeiner, director), Synthetic Chemistry (Core D, Mark Kurth, director), and Cell & Tissue Bioassays (Core E, Peter Haggie, director). Projects to utilize the cores include the discovery of modulators of epithelial ion transporters (CFTR, CaCCs, ENaC, NKCC, potassium channels), epithelial cell mucin secretion, and Pseudomonas biofilm formation. Other projects to utilize the cores include research on mechanisms of lung disease in CF. The general goal of the research to be enhanced by the Core Center is to develop new small-molecule therapies for CF that can be translated into the clinic.